WO2011001634A1 - Method for improving bioavailability of latanoprost - Google Patents
Method for improving bioavailability of latanoprost Download PDFInfo
- Publication number
- WO2011001634A1 WO2011001634A1 PCT/JP2010/004179 JP2010004179W WO2011001634A1 WO 2011001634 A1 WO2011001634 A1 WO 2011001634A1 JP 2010004179 W JP2010004179 W JP 2010004179W WO 2011001634 A1 WO2011001634 A1 WO 2011001634A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- latanoprost
- eye drop
- drop composition
- organic amine
- aqueous
- Prior art date
Links
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 title claims abstract description 120
- 229960001160 latanoprost Drugs 0.000 title claims abstract description 96
- 238000000034 method Methods 0.000 title claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 81
- 239000003889 eye drop Substances 0.000 claims abstract description 56
- 150000001412 amines Chemical class 0.000 claims abstract description 38
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 8
- 206010030043 Ocular hypertension Diseases 0.000 claims abstract description 6
- 229960000281 trometamol Drugs 0.000 claims description 31
- -1 polyethylene Polymers 0.000 claims description 19
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 19
- 239000003755 preservative agent Substances 0.000 claims description 17
- 239000004698 Polyethylene Substances 0.000 claims description 15
- 229920000573 polyethylene Polymers 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000012530 fluid Substances 0.000 claims description 8
- 230000002708 enhancing effect Effects 0.000 claims description 7
- 239000006172 buffering agent Substances 0.000 claims description 6
- 239000012611 container material Substances 0.000 claims description 6
- 239000002736 nonionic surfactant Substances 0.000 claims description 6
- 239000002997 ophthalmic solution Substances 0.000 claims description 4
- 239000012085 test solution Substances 0.000 description 25
- 229940002639 xalatan Drugs 0.000 description 19
- 241000283973 Oryctolagus cuniculus Species 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 150000003180 prostaglandins Chemical class 0.000 description 11
- 210000001742 aqueous humor Anatomy 0.000 description 10
- 239000013065 commercial product Substances 0.000 description 8
- 230000035515 penetration Effects 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960000686 benzalkonium chloride Drugs 0.000 description 6
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- LSIXBBPOJBJQHN-UHFFFAOYSA-N 2,3-Dimethylbicyclo[2.2.1]hept-2-ene Chemical compound C1CC2C(C)=C(C)C1C2 LSIXBBPOJBJQHN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000004397 blinking Effects 0.000 description 4
- 230000004410 intraocular pressure Effects 0.000 description 4
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 4
- 229920000136 polysorbate Polymers 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 238000011200 topical administration Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229960004458 tafluprost Drugs 0.000 description 3
- WSNODXPBBALQOF-VEJSHDCNSA-N tafluprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(F)(F)COC1=CC=CC=C1 WSNODXPBBALQOF-VEJSHDCNSA-N 0.000 description 3
- 241000282320 Panthera leo Species 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 230000003266 anti-allergic effect Effects 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 238000010101 extrusion blow moulding Methods 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 230000009931 harmful effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000010102 injection blow moulding Methods 0.000 description 2
- 230000000622 irritating effect Effects 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- 229940068965 polysorbates Drugs 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- HNPFPERDNWXAGS-LZCJLJQNSA-N (e)-7-[3,5-dihydroxy-2-(3-hydroxy-5-phenylpentyl)cyclopentyl]hept-5-enoic acid Chemical compound C=1C=CC=CC=1CCC(O)CCC1C(O)CC(O)C1C\C=C\CCCC(O)=O HNPFPERDNWXAGS-LZCJLJQNSA-N 0.000 description 1
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- NXYQWAUYFQDQFP-UHFFFAOYSA-N 2h-oxazine;pyridine-2-carboxylic acid Chemical compound N1OC=CC=C1.OC(=O)C1=CC=CC=N1 NXYQWAUYFQDQFP-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 101100256637 Drosophila melanogaster senju gene Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229920002292 Nylon 6 Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000003560 epithelium corneal Anatomy 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- XXUPXHKCPIKWLR-JHUOEJJVSA-N isopropyl unoprostone Chemical compound CCCCCCCC(=O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(=O)OC(C)C XXUPXHKCPIKWLR-JHUOEJJVSA-N 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229960004811 pemirolast potassium Drugs 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- NMMVKSMGBDRONO-UHFFFAOYSA-N potassium;9-methyl-3-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound [K+].CC1=CC=CN(C2=O)C1=NC=C2C1=NN=N[N-]1 NMMVKSMGBDRONO-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 1
- 229960002368 travoprost Drugs 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229950008081 unoprostone isopropyl Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a method for improving ocular bioavailability of latanoprost by adding an organic amine to an aqueous eye drop composition containing latanoprost. The invention further relates to an aqueous eye drop composition in which a better ocular bioavailability of latanoprost is achieved by adding an organic amine, and to a method for treating ocular hypertension and glaucoma by administering said composition to a subject in need of such treatment.
Description
The present invention relates to a method for improving ocular bioavailability of latanoprost by adding an organic amine to an aqueous eye drop composition containing latanoprost. The invention further relates to an aqueous eye drop composition in which a better ocular bioavailability/penetration of latanoprost is achieved by adding an organic amine to the aqueous eye drop composition containing latanoprost, and to a method for treating ocular hypertension and glaucoma by administering said composition to a subject in need of such treatment. The composition is well tolerated.
Like other prostaglandin derivatives, such as isopropyl unoprostone, tafluprost or travoprost, latanoprost is a highly lipophilic medicament. The concentration of latanoprost used for the treatment of glaucoma is very low, approximately 0.005 % (w/v). However, although latanoprost is effective in low amounts, there is still a need to reduce that minor amount to its effective minimum to be administered onto the eye surface. On the other hand, when the amount of the active agent in an eye drop composition is lowered, a balanced but sufficient penetration may become critical or impossible to obtain repeatedly and safely.
Adjuvant agents are included in aqueous eye drop composition in order to achieve sufficiently stable and effective eye drops for the desired purposes. Preservatives have been included in aqueous eye drop compositions not only for their antimicrobial effect but also for their stabilising and homogenizing interactions with the other ingredients. However, preservatives are also known as the major etiology of keratoconjuctive disorders, and for safety purposes it is preferred that the concentration of preservatives, such as those of benzalkonium chloride (BAK) type, is as low as possible. Animal studies and in vitro studies have demonstrated that preservatives such as BAK cause harmful effects on several eye tissues, including the tear film, cornea, conjunctiva and trabecular cells (Baudouin C., Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma. Acta Ophthalmol 2008; 86:716-726 (Non-Patent Document 1)). Evidence from some rabbit and human studies has also suggested that the presence of BAK may affect the corneal epithelium layer and thus increase the transcorneal penetration of poorly permeable drugs. However, a recent study has shown that the corneal penetration into rabbit aqueous humor is comparable between BAK-preserved and preservative-free tafluprost, which is another member in the family of prostaglandin derivatives (Pellinen P, Lokkila J., Corneal penetration into rabbit aqueous humor is comparable between preserved and preservative-free tafluprost. Ophthalmic Res 2009; 41:118-122(Non-Patent Document 2)). The dual role of preservatives (both antimicrobial and stabilizing/solubilizing effects) has lead to difficulties e.g. in preparing stable, preservative-free unit dose eye drop preparations.
Nonionic surfactants and antioxidants have been added to ophthalmic aqueous prostaglandin derivative solutions e.g. in order to prevent lowering of concentration of said prostaglandin derivatives. The latanoprost composition of WO2004/037267 (Sucampo) (Patent Document 1) comprises polysorbate or polysorbate and EDTA, but substantially no BAK. In EP 1321144 (Santen) (Patent Document 2), nonionic surfactants, especially polysorbates, have been found to prevent a prostaglandin derivative from being adsorbed to resinous container walls. The use of nonionic surfactants has been almost inavoidable in ophthalmic aqueous compositions comprising prostaglandin derivatives, especially if a preservative-free aqueous composition has been desired to be produced.
Organic amines have been used in several ophthalmic compositions, mostly as buffers and pH adjusting agents. Japanese Patent Laying-Open No.2003-146881 (Toyo) (Patent Document 3) discloses the prevention of precipitation of anti-allergic pemirolast potassium using trometamol as buffering agent. According to Japanese Patent Laying-Open No.2003-327530 (Sankyo) (Patent Document 4) the preservative effect of a cationic disinfectant such as benzalkonium chloride can be enhanced with trometamol. Incorporating trometamol with a non-ionic surfactant into a suspension-type preparation of an oxazine-picolinic acid has been found to result in suppression of the adhesion of the active ingredient (WO2008/111630 (Santen) (Patent Document 5)). An antiseptic ophthalmic composition free from irritation to eyes can be formulated by including i.a. trometamol in the composition (Japanese Patent Laying-Open No.2004-002364 (Lion) (Patent Document 6); Japanese Patent Laying-Open No.2003-300871 (Lion) (Patent Document 7) and Japanese Patent Laying-Open No.2003-206241 (Teika) (Patent Document 8). According to US2003/0055051 (Wakamoto) (Patent Document 9) an excellent but less stimulative ophthalmic anti-inflammatory effect can be obtained by adding trometamol to an ophthalmic preparation. In Japanese Patent Laying-Open No.11-302162 (Kissei) (Patent Document 10), a better anti-allergic effect of the active ingredient is obtained by incorporating trometamol. Promotion of intraocular penetration of a phenylacetic acid NSAID-compound is possible from a composition containing trometamol (EP 1808170 (Senju) (Patent Document 11). According to EP 1916002 (Santen) (Patent Document 12), degradation of a thermally unstable medicament, such as latanoprost, can be prevented by adding an organic amine such as trometamol.
However, despite of the above mentioned several references of eye drop formulations and various organic amines, there is no disclosure or suggestion that adding an organic amine to an ophthalmic aqueous preservative-free composition, wherein the active ingredient is highly lipophilic like latanoprost could cause a better transcorneal penetration of the latter and hence improved ocular bioavailability of latanoprost in relation to the reduced administered amount.
Baudouin C., Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma. Acta Ophthalmol 2008; 86:716-726
Pellinen P, Lokkila J., Corneal penetration into rabbit aqueous humor is comparable between preserved and preservative-free tafluprost. Ophthalmic Res 2009; 41:118-122
The present invention seeks to solve the above problems, and it is therefore an object of the present invention to provide a method for improving ocular bioavailability of preservative-free latanoprost in an aqueous eye drop composition by adding an organic amine to the eye drop composition containing latanoprost.
Another object of the invention is a preservative-free aqueous eye drop composition comprising latanoprost, wherein the ocular bioavailability of latanoprost is improved by adding an organic amine.
A further object of the invention is a method for treating ocular hypertension and glaucoma by administering to a subject in need of such treatment an effective amount of an aqueous preservative-free eye drop composition comprising latanoprost, wherein the ocular bioavailability of latanoprost is improved by adding an organic amine.
The present invention is directed to a method for improving ocular bioavailability of latanoprost from an aqueous eye drop composition by adding an organic amine to the eye drop composition containing latanoprost.
In this regard, it is preferred that the organic amine is an organic amine having a hydroxy group, and the organic amine having a hydroxy group is particularly preferably trometamol.
Further, in these methods according to the present invention, it is also preferred that the aqueous eye drop composition contains substantially no preservatives.
It is also preferred that the aqueous eye drop composition contains viscosity enhancing agents.
The present invention is also directed to an aqueous eye drop composition comprising latanoprost, wherein the ocular bioavailability of latanoprost is improved by adding an organic amine.
In this regard, it is preferred that the organic amine is an organic amine having a hydroxy group, and the organic amine having a hydroxy group is particularly preferably trometamol.
Further, in the aqueous eye drop composition comprising latanoprost according to the present invention, it is also preferred that the composition contains substantially no preservatives.
It is also preferred that the composition contains viscosity enhancing agents.
In the aqueous eye drop composition comprising latanoprost according to the present invention, it is preferred that the composition comprises 0.0025 to 0.005 % (w/v) latanoprost, 0.1 to 1 % (w/v) trometamol, optionally buffering agents, pH adjusters, tonicity and viscosity enhancing agents conventionally used in ophthalmic solutions, and substantially no preservatives, in a unit dose container or fluid dispenser consisting essentially of polyethylene or in contact with container material consisting essentially of polyethylene.
Moreover, the present invention is also directed to a method for treating ocular hypertension and glaucoma by administering to a subject in need of such treatment an effective amount of an aqueous eye drop composition comprising latanoprost, wherein the ocular bioavailability of latanoprost is improved by adding an organic amine.
According to the present invention it has now been found that ocular bioavailability of latanoprost in an aqueous eye drop composition can be improved by adding an organic amine to the aqueous eye drop composition containing latanoprost. This invention enables to provide homogenous and stable, preservative-free aqueous ophthalmic latanoprost solution as a sterile, preferably unit dose type formulation. The aqueous eye drop composition according to the invention is also less irritative to the eye than the currently available commercial product. The aqueous eye drop composition of the present invention also remains stable at room temperature, contrary to the currently available commercial product which requires cold storage (at 2-8 oC).
The present invention is a method for improving ocular bioavailability of latanoprost from an aqueous eye drop composition by adding an organic amine to the eye drop composition containing latanoprost. The present invention also provides an aqueous eye drop composition comprising latanoprost, wherein the ocular bioavailability of latanoprost is improved by adding an organic amine. Furthermore, the present invention also provides a method for treating ocular hypertension and glaucoma by administering to a subject in need of such treatment an effective amount of an aqueous eye drop composition comprising latanoprost, wherein the ocular bioavailability of latanoprost is improved by adding an organic amine.
This invention enables to provide homogenous and stable, preservative-free aqueous ophthalmic latanoprost solution as a sterile, preferably unit dose type formulation. The aqueous eye drop composition according to the invention is also less irritative to the eye than the currently available commercial product. The aqueous eye drop composition of the present invention also remains stable at room temperature, contrary to the currently available commercial product which requires cold storage (at 2-8 oC).
Within this description, "substantially no preservatives" or "preservative-free" means that the composition(solution) contains absolutely no preservatives, or the composition(solution) contains preservatives at a concentration that is undetectable or does not provide a preservative effect.
"Bioavailability" refers to the degree and rate at which a drug is absorbed and made available in the target tissue. "Ocular bioavailability" refers more specifically to the concentration of a drug in the aqueous humor after topical administration of a drug comprising the aqueous eye drop composition.
"Stability" refers to chemical and physical stability of a drug comprising the aqueous eye drop composition.
The ingredients other than latanoprost and an organic amine may not be particularly limited as far as latanoprost is homogenously and stably dissolved in the aqueous solution. However, it is notable that nonionic surfactants (polysorbates, cremophores etc.) or preservatives are not required in the aqueous eye drop composition of the invention to provide a stable and bioavailable formulation for use in a single dose form.
The concentration of latanoprost in the aqueous eye drop composition and dosing frequency may vary according to the type and condition of the subject to be treated. For example, an aqueous eye drop composition containing latanoprost at a concentration of 0.0005 to 0.01 % (w/v), preferably 0.001 to 0.0075 % (w/v), more preferably 0.0025 to 0.005 % (w/v) may be instilled 1 to 4 times, preferably 1 to 2 times, and more preferably 1 time a day.
As the invention provides improved ocular bioavailability and intraocular pressure(IOP) lowering effect of latanoprost, the amount of latanoprost in the aqueous eye drop composition can be lowered compared to the prior art products, still achieving an effective product.
The organic amine is a water-soluble organic amine, examples of which include organic amines having a hydroxy group, such as monoethanolamine, diethanolamine, triethanolamine, trometamol and meglumine. A preferred organic amine is trometamol.
The concentration of the organic amine is for example in the case of trometamol preferably in the range of from 0.01 % to 1 % (w/v), more preferably from 0.05 to 0.75 % (w/v).
The aqueous eye drop composition according to the invention may also comprise conventional excipients used in ophthalmic compositions, such as buffering agents, solvents, pH adjusters, tonicity agents, viscocity enhancers and the like. Preferred excipients for use in the aqueous eye drop composition of the present invention are viscosity enhancers. Suitable viscosity enhancers include but are not limited to cellulose derivatives, such as hydroxypropyl methylcellulose, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinylalcohols, dextrans and polyacrylic acids. Examples of suitable buffering agents include but are not limited to sodium dihydrogen phosphate dihydrate, boric acid, borax, citric acid, or e-aminocaproic acid. Specific examples of tonicity agents include but are not limited to glycerol, sorbitol, mannitol and other sugar alcohols, propylene glycol, sodium chloride, potassium chloride and calcium chloride
The pH of the aqueous ophthalmic latanoprost solution according to the invention is preferably from 4 to 8, more preferably from 5 to 7. As pH adjusters, common pH adjusting agents such as sodium hydroxide and/or hydrochloric acid may be used.
The aqueous ophthalmic latanoprost solution according to the invention is preferably packaged in a container consisting essentially of polyethylene or in contact with material consisting essentially of polyethylene. The container material may contain minor amounts of other materials than polyethylene, for example polypropylene, polyethylene terephthalate, polyvinyl chloride, acrylic resins, polystyrene, polymethyl methacrylate and nylon 6. The amount of said materials is preferably no more than about 5 to 10 % of the total container material.
Containers for packaging and storing the aqueous ophthalmic latanoprost solution according to the invention include all container forms suitable for user-friendly topical ophthalmic delivery, preferably those of unit dose form. Consequently, the containers may be selected for example from the group consisting of bottles, tubes, ampoules, pipettes and fluid dispensers for dispensing minute amounts of sterile fluid.
The containers for the aqueous ophthalmic latanoprost solution according to the invention are preferably manufactured by extrusion blow moulding method. Extrusion blow moulding gives smoother inner surface of the container compared to injection blow moulding, which is commonly used to manufacture for example polyethylene multidose bottles. The smoother inner surface gives better chemical stability of prostaglandins in the polyethylene container compared to polyethylene container manufactured by injection blow moulding. Furthermore, when single-dose containers are used, they are sterilized during the moulding process by heat and no additional sterilization of containers is needed, which also improves stability of prostaglandins in a single-dose container. Conventional techniques for sterilization of prostaglandin eye drop products consist of treatment of the empty plastic bottles with highly toxic ethylene oxide gas before filling-in the solution (see EP 1825855(Santen)) and EP 1349580(Novartis)). The much smoother sterilization process used in the preparation of the eye drop composition of the present invention (heat sterilization during the filling process) is however more recommendable for a unit dose preparation especially in polyethylene containers.
Although unit dose containers are preferred for the purposes of the invention, the aqueous ophthalmic latanoprost solution according to the invention remains soluble, stable and bioavailable also in fluid dispensers for dispensing of minute amounts of germ-free fluid or in any other container-type wherein the aqueous ophthalmic latanoprost solution is in contact with container material consisting essentially of polyethylene. Such fluid dispensers are disclosed for example in US 5,614,172 (Ursapharm).
The preservative-free aqueous ophthalmic latanoprost solution according to the invention can be stored at room temperature in the above mentioned suitable containers, including unit dose pipettes and dispensers. Stability studies have shown that a preservative-free aqueous ophthalmic latanoprost solution according to the invention is stable in a polyethylene container for a long time, at least for 9 months at 5 oC and at 25 oC.
In the aqueous eye drop composition comprising latanoprost according to the present invention, it is preferred that the composition comprises 0.0025 to 0.005 % (w/v) latanoprost, 0.1 to 1 % (w/v) trometamol, optionally buffering agents, pH adjusters, tonicity and viscosity enhancing agents conventionally used in ophthalmic solutions, and substantially no preservatives, in a unit dose container or fluid dispenser consisting essentially of polyethylene or in contact with container material consisting essentially of polyethylene.
The following examples illustrate the invention without limiting the same in any way.
Male albino rabbits of New Zealand White strain were used. In each rabbit, one eye was dosed topically with one of the test solution A, B, C or D and the other eye with the reference solution (Xalatan). The latanoprost-trometamol ratios used in the test solutions A, B, C and D were as follows:
(1) Test solution A
Latanoprost - Trometamol ratio: 0.013 (Latanoprost concentration 0.005%)
(2) Test solution B
Latanoprost - Trometamol ratio: 0.017 (Latanoprost concentration 0.005%)
(3) Test solution C
Latanoprost - Trometamol ratio: 0.017 (Latanoprost concentration 0.005%)
(4) Test Solution D
Latanoprost - Trometamol ratio: 0.029 (Latanoprost concentration 0.0035%)
The rabbits were sacrificed at each time point (4 animals per treatment per time point) and aqueous humor sample was taken. The concentration of latanoprost acid was measured using the HPLC/MS method. The results of test solution A, B, C and D are shown in Figures 1A, 1B, 1C and 1D, respectively.
(1) Test solution A
Latanoprost - Trometamol ratio: 0.013 (Latanoprost concentration 0.005%)
(2) Test solution B
Latanoprost - Trometamol ratio: 0.017 (Latanoprost concentration 0.005%)
(3) Test solution C
Latanoprost - Trometamol ratio: 0.017 (Latanoprost concentration 0.005%)
(4) Test Solution D
Latanoprost - Trometamol ratio: 0.029 (Latanoprost concentration 0.0035%)
The rabbits were sacrificed at each time point (4 animals per treatment per time point) and aqueous humor sample was taken. The concentration of latanoprost acid was measured using the HPLC/MS method. The results of test solution A, B, C and D are shown in Figures 1A, 1B, 1C and 1D, respectively.
Figures 1A-1C illustrate absorption of latanoprost from preservative-free test solutions with different latanoprost-trometamol ratio into aqueous humor of rabbit eye in comparison with Xalatan, when latanoprost concentration in the test solution was the same as in Xalatan. In figure 1D, latanoprost concentration in the test solution was 70 % of the latanoprost concentration in Xalatan.
In Figures 1A-1D it can be seen that by increasing the latanoprost-trometamol ratio in preservative-free test solutions transcorneal penetration of latanoprost into aqueous humor of rabbit eye is improved.
Spraque-Dawley rats were used to study the effects of ophthalmic solutions on the IOP. The test solutions E and F were dosed topically (5 ml) either as a single instillation or repeated instillations (for eight days) onto one eye and the reference solution (commercial Xalatan) onto the other. The latanoprost-trometamol ratios used in the test solutions E and F were as follows:
(1) Test solution E
Latanoprost - Trometamol ratio: 0.020 (latanoprost concentration the same as in Xalatan)
(2) Test solution F
Latanoprost - Trometamol ratio: 0.029 (latanoprost concentration 70% of Xalatan)
(1) Test solution E
Latanoprost - Trometamol ratio: 0.020 (latanoprost concentration the same as in Xalatan)
(2) Test solution F
Latanoprost - Trometamol ratio: 0.029 (latanoprost concentration 70% of Xalatan)
Six to twelve animals were used per study. IOP was measured prior to dosing at 0 h and 2, 4, 6 and 8 hours (or additional 10 hours) after the dosing. Measurement was performed with a TonoLab rebound tonometer.
Figures 2A - 2B show IOP after single topical administration in rats when preservative-free test solutions with different latanoprost-trometamol ratios and different latanoprost concentrations were used in comparison with Xalatan. Figures 2B - 2C compare the effect on IOP after single administration and repeated administrations (for eight days) of the formulation containing Latanoprost - Trometamol ratio: 0.029 (latanoprost concentration 70% of Xalatan).
From the results it can be seen that the commercial product causes an immediate increase in the IOP and the IOP lowering effect is seen only after several (6 to 8) hours. The compositions according to the invention do not provide a harmful initial increase in the IOP which is common when eye prostaglandins like latanoprost are administered. With the compositions according to the invention the IOP lowering effect starts earlier than with the current commercial product. The IOP lowering effect stays at the same level after repeated instillation as it is after single instillation which loss of efficacy may often be the case with repeated administration of eye prostaglandins like latanoprost. Furthermore, the IOP lowering effect of the composition according to the invention is better than that of the commercial product, even with a latanoprost concentration of only 70 % of the amount of latanoprost in the commercial product.
Blinking frequency was studied as a parameter for acute eye irritation of Xalatan and preservative-free latanoprost according to the present invention in albino rabbits of New Zealand White strain. Six rabbits were used per treatment group, and in each rabbit, one eye was dosed topically with one of the test solutions and the other eye served as a non-treated control. Test solutions were instilled 10 times at 30 min intervals during one day. Blinking frequency was measured for one minute after the 1st and 10th instillation. The results are shown in Table 1.
The commercial Xalatan caused a statistically significantly higher blinking frequency compared to non-treated eye after the tenth instillation. The treated eye blinked more frequently than the non-treated eye. In the preservative-free Latanoprost group no significant difference between eyes was detected. In addition, the difference between Xalatan and Latanoprost groups was statistically significant after the tenth instillation when the differences were compared (non-treated eyes were subtracted from the treated eyes p=0.0005, students t-test) blinking frequency being higher in Xalatan group. The compositions according to the invention are better tolerated.
The stability of preservative-free latanoprost in low density polyethylene containers was studied for 9 months at 5 oC and 25 oC. The composition of the preservative-free aqueous latanoprost formulation in the study was 0.003 % latanoprost, 0.3 % trometamol, 0.9 % sodium chloride and hydrochloric acid / sodium hydroxide to adjust the pH to 7.0.
0.3 ml of the composition prepared above was filled in the body part of the polyethylene unit dose container and sealed by heating with the upper part of the container. The containers were packaged into paper coated aluminium-polyethylene foil and stored in refrigerator or incubator.
The concentration of latanoprost was measured by HPLC/UV. The results in comparison to time zero value are presented in figures 3A - 3B. The results show that latanoprost concentration remains at the same level at 5 oC and 25 oC at least for nine (9) months.
Claims (12)
- A method for improving ocular bioavailability of latanoprost from an aqueous eye drop composition by adding an organic amine to the eye drop composition containing latanoprost.
- The method according to claim 1, wherein the organic amine is an organic amine having a hydroxy group.
- The method according to claim 2, wherein the organic amine having a hydroxy group is trometamol.
- The method according to claim 1, wherein the aqueous eye drop composition contains substantially no preservatives.
- The method according to claim 1, wherein the aqueous eye drop composition contains viscosity enhancing agents.
- An aqueous eye drop composition comprising latanoprost, wherein the ocular bioavailability of latanoprost is improved by adding an organic amine.
- The aqueous eye drop composition according to claim 6 wherein the organic amine is an organic amine having a hydroxy group.
- The aqueous eye drop composition according to claim 7, wherein the organic amine having a hydroxy group is trometamol.
- The aqueous eye drop composition according to claim 7 which contains substantially no preservatives or non-ionic surfactants.
- The aqueous eye drop composition according to claim 6 which further comprises viscosity enhancing agents.
- The aqueous eye drop composition according to claim 6, which comprises 0.0025 to 0.005 % (w/v) latanoprost, 0.1 to 1 % (w/v) trometamol, optionally buffering agents, pH adjusters, tonicity and viscosity enhancing agents conventionally used in ophthalmic solutions, and substantially no preservatives, in a unit dose container or fluid dispenser consisting essentially of polyethylene or in contact with container material consisting essentially of polyethylene.
- A method for treating ocular hypertension and glaucoma by administering to a subject in need of such treatment an effective amount of an aqueous eye drop composition comprising latanoprost, wherein the ocular bioavailability of latanoprost is improved by adding an organic amine.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2766269A CA2766269C (en) | 2009-06-30 | 2010-06-23 | Method for improving bioavailability of latanoprost |
| EA201270097A EA022390B1 (en) | 2009-06-30 | 2010-06-23 | Method for improving bioavailability of latanoprost |
| SG2011091741A SG176800A1 (en) | 2009-06-30 | 2010-06-23 | Method for improving bioavailability of latanoprost |
| JP2011551134A JP5695580B2 (en) | 2009-06-30 | 2010-06-23 | How to improve the bioavailability of latanoprost |
| EP10793808.6A EP2448589A4 (en) | 2009-06-30 | 2010-06-23 | Method for improving bioavailability of latanoprost |
| UAA201200886A UA107466C2 (en) | 2009-06-30 | 2010-06-23 | Method for improving bioavailability of latanoprost |
| CN201080028960.9A CN102802633B (en) | 2009-06-30 | 2010-06-23 | For improving the method for bioavailability of latanoprost |
| US13/381,631 US20120107376A1 (en) | 2009-06-30 | 2010-06-23 | Method for improving bioavailability of latanoprost |
| HK13100192.1A HK1172849A1 (en) | 2009-06-30 | 2013-01-07 | Method for improving bioavailability of latanoprost |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09397519.1 | 2009-06-30 | ||
| EP09397519A EP2269575A1 (en) | 2009-06-30 | 2009-06-30 | Method for improving bioavailability of latanoprost |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011001634A1 true WO2011001634A1 (en) | 2011-01-06 |
Family
ID=41137869
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2010/004179 WO2011001634A1 (en) | 2009-06-30 | 2010-06-23 | Method for improving bioavailability of latanoprost |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US20120107376A1 (en) |
| EP (2) | EP2269575A1 (en) |
| JP (1) | JP5695580B2 (en) |
| KR (1) | KR20120095341A (en) |
| CN (1) | CN102802633B (en) |
| CA (1) | CA2766269C (en) |
| EA (1) | EA022390B1 (en) |
| HK (1) | HK1172849A1 (en) |
| MY (1) | MY157434A (en) |
| SG (1) | SG176800A1 (en) |
| UA (1) | UA107466C2 (en) |
| WO (1) | WO2011001634A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GR1008483B (en) * | 2013-12-23 | 2015-05-12 | Rafarm Α.Ε.Β.Ε., | Ophthalmic pharmaceutiacl composition and process for the preparation thereof |
| WO2018033854A1 (en) | 2016-08-15 | 2018-02-22 | Santen Pharmaceutical Co., Ltd. | Ophthalmic composition and a method for treating ocular hypertension and glaucoma |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007015510A1 (en) * | 2005-08-02 | 2007-02-08 | Santen Pharmaceutical Co., Ltd. | Method for prevention of degradation of thermally unstable substance |
| WO2008096804A1 (en) * | 2007-02-07 | 2008-08-14 | Teika Pharmaceutical Co., Ltd. | Eye drop preparation comprising latanoprost |
| JP2009040749A (en) * | 2007-08-10 | 2009-02-26 | Kaken Pharmaceut Co Ltd | Latanoprost ophthalmic agent |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5040706A (en) * | 1989-03-17 | 1991-08-20 | Insite Vision, Inc. | Liquid droplet dispensing apparatus |
| JPH03146881A (en) | 1989-11-01 | 1991-06-21 | Fanuc Ltd | Loading/unloading structure for holding frame of printed board |
| JPH0689576B2 (en) | 1989-12-30 | 1994-11-09 | 株式会社第一ホーム | Joist fixing device |
| JPH042364A (en) | 1990-04-19 | 1992-01-07 | Olympus Optical Co Ltd | Fistula forming tube |
| DE4027320C2 (en) | 1990-08-29 | 1993-09-30 | Ursapharm Arzneimittel Gmbh | Fluid dispenser for aseptic fluid |
| JP3659801B2 (en) | 1998-04-21 | 2005-06-15 | キッセイ薬品工業株式会社 | Tranilast aqueous solution formulation |
| KR100854056B1 (en) | 2000-09-13 | 2008-08-26 | 산텐 세이야꾸 가부시키가이샤 | Eye drops |
| US20030055052A1 (en) | 2000-11-10 | 2003-03-20 | Stefan Peters | FAP-activated anti-tumor compounds |
| TW586946B (en) | 2000-12-22 | 2004-05-11 | Novartis Ag | Process to improve stability |
| US7074827B2 (en) | 2002-10-24 | 2006-07-11 | Sucampo Ag (Usa) Inc. | Method for treating ocular hypertension and glaucoma |
| CN1993118B (en) | 2004-11-05 | 2010-06-16 | 千寿制药株式会社 | Aqueous eye drops with accelerated intraocular migration permeability |
| KR101305649B1 (en) | 2004-12-09 | 2013-09-09 | 산텐 세이야꾸 가부시키가이샤 | Product containing prostaglandin having fluorine atom in molecule |
| CA2630304C (en) * | 2005-12-09 | 2012-04-10 | Teva Pharmaceutical Industries Ltd. | Aqueous dispersions and solutions of difficult to dissolve compounds and methods of their preparation |
| TWI465236B (en) | 2007-03-13 | 2014-12-21 | 參天製藥股份有限公司 | Suspended aqueoue formulation of pirenoxine |
| WO2009007828A1 (en) * | 2007-07-11 | 2009-01-15 | Ophthalmopharma Ag | Complexes of prostaglandin derivatives and monosubstituted, charged beta-cyclodextrins |
-
2009
- 2009-06-30 EP EP09397519A patent/EP2269575A1/en not_active Withdrawn
-
2010
- 2010-06-23 EP EP10793808.6A patent/EP2448589A4/en not_active Withdrawn
- 2010-06-23 MY MYPI2011006155A patent/MY157434A/en unknown
- 2010-06-23 KR KR1020127001350A patent/KR20120095341A/en active Search and Examination
- 2010-06-23 JP JP2011551134A patent/JP5695580B2/en not_active Expired - Fee Related
- 2010-06-23 WO PCT/JP2010/004179 patent/WO2011001634A1/en active Application Filing
- 2010-06-23 SG SG2011091741A patent/SG176800A1/en unknown
- 2010-06-23 UA UAA201200886A patent/UA107466C2/en unknown
- 2010-06-23 US US13/381,631 patent/US20120107376A1/en not_active Abandoned
- 2010-06-23 EA EA201270097A patent/EA022390B1/en not_active IP Right Cessation
- 2010-06-23 CN CN201080028960.9A patent/CN102802633B/en not_active Expired - Fee Related
- 2010-06-23 CA CA2766269A patent/CA2766269C/en not_active Expired - Fee Related
-
2013
- 2013-01-07 HK HK13100192.1A patent/HK1172849A1/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007015510A1 (en) * | 2005-08-02 | 2007-02-08 | Santen Pharmaceutical Co., Ltd. | Method for prevention of degradation of thermally unstable substance |
| WO2008096804A1 (en) * | 2007-02-07 | 2008-08-14 | Teika Pharmaceutical Co., Ltd. | Eye drop preparation comprising latanoprost |
| JP2009040749A (en) * | 2007-08-10 | 2009-02-26 | Kaken Pharmaceut Co Ltd | Latanoprost ophthalmic agent |
Also Published As
| Publication number | Publication date |
|---|---|
| MY157434A (en) | 2016-06-15 |
| CA2766269A1 (en) | 2011-01-06 |
| CN102802633B (en) | 2016-01-20 |
| EA201270097A1 (en) | 2012-05-30 |
| UA107466C2 (en) | 2015-01-12 |
| CA2766269C (en) | 2018-04-03 |
| JP2012532091A (en) | 2012-12-13 |
| KR20120095341A (en) | 2012-08-28 |
| SG176800A1 (en) | 2012-01-30 |
| EA022390B1 (en) | 2015-12-30 |
| EP2448589A4 (en) | 2013-04-17 |
| JP5695580B2 (en) | 2015-04-08 |
| CN102802633A (en) | 2012-11-28 |
| EP2448589A1 (en) | 2012-05-09 |
| HK1172849A1 (en) | 2013-05-03 |
| EP2269575A1 (en) | 2011-01-05 |
| US20120107376A1 (en) | 2012-05-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10864159B2 (en) | Method and composition for treating ocular hypertension and glaucoma | |
| US20210128458A1 (en) | Ophthalmic compositions containing a nitric oxide releasing prostamide | |
| CA2766269C (en) | Method for improving bioavailability of latanoprost |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WWE | Wipo information: entry into national phase |
Ref document number: 201080028960.9 Country of ref document: CN |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10793808 Country of ref document: EP Kind code of ref document: A1 |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2011551134 Country of ref document: JP |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2766269 Country of ref document: CA |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 13381631 Country of ref document: US |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2010793808 Country of ref document: EP |
|
| ENP | Entry into the national phase |
Ref document number: 20127001350 Country of ref document: KR Kind code of ref document: A |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 201270097 Country of ref document: EA |